Spiro 2h-3,1-benzoxazine derivatives

ABSTRACT

The disclosure is directed to derivatives of spiro 2H-3,1benzoxazine prepared by reacting a mixture of 2-amino-5chlorophenylbenzyl alcohol and an appropriately substituted piperidone, isatin or quinuclidone derivative. The compounds are useful as anti-amebics in vitro, and some are central nervous depressants.

United States Patent [1 1 Diebold et al.

DERIVATIVES [75] Inventors: James L Diebold, Broomall; Milton Wolf, West Chester, both of Pa.

[ SPIRO 2H-3,1-BENZOXAZINE [73] Assignee: Aiiierican il ome lroductscorpora tion, New York, N.Y.

[22] Filed: March 12, 1971 [21] Appl. No.: 123,849

[ 1 Jan. 16, 1973 [56] 1 References Cited UNITED STATES PATENTS 3,600,2l4 8/l 97l Feinauer ..260/244 Primary Exdminerl-larry l Moatz Attorney-Vito Victor Bellino, Andrew Kafko, Joseph 1 Martin Weigman and Dwight J. Potter [57 ABSTRACT The disclosure isdirected to derivatives of spiro 2H- 3,l-ben'zoxazine prepared by reacting a mixture of 2- amino-5-chlorophenylbenzyl propriately substituted piperidone, isatin or quinuclidone derivative. The compounds are useful as antiamebics in vitro, and some are central nervous depressants.

5 Claims, N0 Drawings alcohol and an apwith a heterocyclo-alkanone in the presence of an acid catalyst. I

The compounds within the purview of the present invention have the following formula:

I 52: 7 I 'l where Xis oxa, thia or -NR"; R is hydrogen or lower alkyl; R is hydrogen, lower alkyl or di(lower)alkylamino- (lower)alkyl;

m is an integer from I to 6; and

n is an integer from 1 to 6 with the proviso that the sum of m and n is no greater than 7.

As defined herein, the terms lower alkyl," "lower alkoxy" and the like describe groups having from one to four carbon atoms.

A typical example of the compounds of this invention which are depicted by structural Formula (I) is 6- chloro-l ,4-dihydro-l '-methyl-4-phenylspiro[2I-I-3, l benzoxazine-Z,4'-piperidine].

The new and useful compounds of this invention may be prepared by the process which is hereinafter schematically illustrated, RR being defined as described above: I

cHoH rhestamn 'maielrals used in the preparaaaa oft he claimed compounds are generally known and can be prepared by well known procedures. The products of the present invention may be prepared by mixing 2- amino-S-chlorophenylbenzyl alcohol (II) with aheterocycloalkanone (III) in the presence of an acid catalyst and heating the mixture for a period of one to thirty hours. When the reaction is complete, the product, a spiro 2H-3,l-benzoxazine. derivative (I), may be separated by standard recovery methods. For instance, the solution may be evaporated and the residue triturated with ether giving a solid. Recrystallization of the solid from benzene affords the pure compound. The acid catalyst may be any of those well known for such purpose, preferably zinc chloride, p-toluene sulfonic acid and the like. The reaction period varies with the reactants and preferably is about 3 to 20 hours. The

reaction temperature is preferably the reflux temperature but lower temperatures may be used with an appropriate longer reaction time as is well understood in the art.

In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vitro effects are tested as follows. The test substance is incorporated and diluted in the aqueous phase of modified Boeck-Drbohlav diphasic medium fortified with rice starch. The medium is inoculated with polybacteria, and a known number of trophozolites of Endameba' histolytica NIH 200. After 48 hours incubation at 35C. the trophozolites are counted. The minimal inhibitory concentration (MIC) expressed in micrograms per milliliter (pg/ml) is the least amount of a test compound that completely inhibits Endameba histolytica. The activity of the compounds is compared against emetinc hydrochloride as a standard. This procedure is suggested in Thompson et al., Antibio. & Chemo. 6, (1956), 337-50. Some of the compounds of the present invention were found to produce a 100 percent kill at an MIC of 15.6 to 125. All of the substances produced better than percent kill at 1000 MIC.

' In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects are tested as follows. The compound is administered orally or intraperitoneally to three mice (14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7 milligrams per kilogram of host body weight (MPK). The animals are watched for a minimum of two hours during which time signs of general stimulation (i.e., increased spontaneous motor activity, hyperactivity on tactile stimulation, twitching), general depression (i.e., decreased spontaneous motor activity, decreased respiration), autonomic activity (i.e., miosis, mydriasis, diarrhea) are noted.

The compounds of this invention induce central nervous system depressant effects at a dose of 127 to 400 MPK.

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers,'the proportion of which is determined by the" solubility and chemical nature of the compound, 5 chosen route of administration and standard phar-; macological practice. For example, they may be administered orally in the form of tablets or capsules con taining such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered, sublingually in the form of troches or lozenges in which the active ingredient is mixed withsugar and corn. syrups; and then dehydrated sufficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intravenously or subcutaneously. For parenteral administration they may be used in the form of a sterile solu' tion containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. It 3 will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. In general. the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the present invention, specific examples of the practice of the invention are hereinafter given. It should be understood, however, that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended 45 claims. In the examples, all temperatures are stated indegrees Centigrade, and the following abbreviations are used: g." for grams, ml." for milliliters, m for gram molecular weight, hrs. for hours, and (11" for phenyl (C 11 EXAMPLE I The following example illustrates the preparation of 6-chloro-l,4-dihydro-1-methyl-4-phenylspiro[2I-I-3,l-

benzoxazine-2,4'-piperidine].

I Cl

i0 .0 2il5:rii.a catalytic amount of zinc chloride and mlfo f xylene is refluxed for 3 hours over a Dean-Stark trap. The solution is evaporated and the residue triturated with ether giving a solid. Recrystallization from benzene affords 6-ch1oro -1,4-dihydro-l-methyl-4-' pheny1spiro[2H-3,1-benzoxazine-2,4'-piperidine] as a crystalline solid (3.6 g.,.Sl percent yield) having a melting point of l 16-1 17 (uncorrected).

Based on the assumed molecular formula c H cm, 0,. it was calculated that the elemental analysis by 'weight would be 69.40 percent carbon, 6.43 percent hydrogen and 8.52 percent nitrogen. The product was analyzed and found to contain 69.49 percent carbon, 6.29 percent hydrogen, and 8.41 percent nitrogen which confirmed the accuracy of the assumed formula. This may be expressed: Anal. Calcd. for C l-l ClN Oz C, 69.40; H, 6.43; N, 8.52.

Found: C, 69.49; H, 6.29; N, 8.41.

The product was analyzed in the foregoing pharmacological procedures and foundto kill 100 percent E. histolytica at a concentration of ug/ml (emetine 0.975) in vitro, and to induce decreased motor activity and decreased respiration at a dose of 127 MPK administered intraperitoneally.

EXAMPLE II The following illustrates the preparation of 1'- benzyl-6-chloro-1,4-dihydro-4-phenylspiro[2H-3,1- benzoxazine-2,3 '-piperidine 1.

2-Amino-5-chlorophenylbenzylalcohol (10.0 g., 0.043 m. and 1-benzy1-3-piperidone(8.13 g., 0.043 m.) are allowed to react in a manner similar to Example I except employing a trace of p-toluene sulfonic as acid catalyst and toluene as solvent. The residue is triturated with ether and pentane and then filtered. The solid which precipitates from the filtrate is recrystallized from benzene-hexane affording l-benzy1-6-chloro-l ,4-

The following illustrates the preparation of 6-chloro- 50 l,4-dihydro-4-phenyl[2H-3. l -benzoxazine-2,3 indolin]-2'-one.

Z-Amino-5 chlorophenylbenzylalcohol (8.0 0.034

a manner similar to Example ll except for a 20 hour reflux time. Recrystallization of the product from dimethylformamide-benzene affords 6-chloro-l,4- dihydro-4-phenyl[2H-3,l-benzoxazine2,3'-indolin]- 2'-one as a crystalline solid which decomposes at 248-249C. (uncorrected).

Anal. Calcd. for c n cm m; c, 69.52;", 4.17; N,

Found: C, 69.81; H. 3.89; N. 7.92.

The product was analyzed in the foregoing analytical procedures and found to kill 91 percent E. hisrolylica at a concentration of L000 ug/ml in vitro (emetine 0.975), and to induce decreased respiration and decreased motor activity at a dose of 400 MPK administered intraperitoneally.

Following the procedure of Example Ill but substitut ing appropriate starting materials, products having the following substituents may be obtained:

The following illustrates the preparation of 6-chlorol,4-dihydro-4-phenylspiro[21-1-3, l -benzoxazine-2,3 I

quinuclidine].

2-Amino-5-chlorophenylbenzylalcohol (5.0 g.,

010215 m.) and 3-quinuclidone (3.0g, 0.0239 m.) are allowed toreact in a manner similar to Example ll. A

solid is obtained upon heating the crude product with hexane. Recrystallization from benzene-hexane affords 65 6-chloro-l ,4-dihydro-4-phenylspirol 2H-3, l -benzoxazine-2,3-quinuelindine] as a crystalline solid having a melting point of l64l 67C (uncorrected). IV

AnaL-Calcd. for C,,H,,,CIN,O: c, 70.46; H, 6.2l;N,

LAN

Found: C, 70.75 H, 5.90; N, 8.14.

45 The product was analyzed in the macological procedures and found to kill lOO percent E. histolytica at a concentration of 15.6 ug/ml in vitro (emetine 0244) and to induce decreased respiration and decreased motor control at a dose of I27 MPK ad- 50 ministered orally.

Following the procedure of Example lV but substituting appropriate starting materials, products hav ing the following substituents may be prepared:

foregoing phar- 

2. A compound as described in claim 1 which is 6-chloro-1,4-dihydro-1''-methyl-4-phenylspiro(2H-3,1-benzoxazine-2,4'' -piperidine).
 3. A compound as described in claim 1 which is 1''-benzyl-6-chloro-1,4-dihydro-4-phenylspiro(2H-3,1-benzoxazine-2,3'' -piperidine).
 4. A compound as described in claim 1 which is 6-chloro-1,4-dihydro-4-phenyl(2H-3,1-benzoxazine-2,3''-indolin)-2''-one.
 5. A compound as described in claim 1 which is 6-chloro-1,4-dihydro-4-phenylspiro(2H-3,1-benzoxazine-2,3''-quinuclidine). 